Compositions and methods for diagnosing and treating cancer and neurodegenerative diseases rlated to beclin-1

Abstract

The present invention relates to antibodies specific for human Beclin-1 protein phosphorylated at position Thr 119 and uses thereof. In particular, these antibodies are useful in diagnosing diseases associated with impaired autophagy including cancer and neurodegenerative diseases. The invention further relates to human Beclin-1 mutated at position 119 with a phospho-mimicking residue and uses thereof for treating cancer and neurodegenerative diseases.

1 .- 17 . (canceled) 
     
     
         18 . A method for diagnosing a neurodegenerative disease in a subject, comprising determining the level of Beclin-1 that is phosphorylated at position Thr 119 in a cell of the subject or a sample obtained therefrom using an antibody having specific binding affinity for a human Beclin-1 phosphorylated at residue Thr 119, or an antigen binding fragment thereof. 
     
     
         19 . A method for diagnosing a neurodegenerative disease in a subject comprising:
 a. obtaining a biological test sample from the subject;   b. contacting the biological test sample with an antibody having specific binding affinity for a human Beclin-1 phosphorylated at residue Thr 119, or an antigen binding fragment thereof, under conditions such that a complex can form between phosphorylated Beclin-1 and the antibody or antigen binding fragment thereof, and quantifying the amount of said complex, thereby quantifying the amount of phosphorylated Beclin-1 in said biological test sample; and   c. comparing the amount of phosphorylated Beclin-1 in said biological test sample to a standard or control sample;   wherein a reduced amount or absence of phosphorylated Beclin-1 in said biological test sample relative to the standard or control sample is indicative of said neurodegenerative disease in said subject.   
     
     
         20 . The method according to  claim 19 , wherein the amount of phosphorylated Beclin-1 is determined by a method selected from the group consisting of immunohistochemistry, immunostaining, immunofluorescence and western blot assay. 
     
     
         21 . The method according to  claim 19 , wherein the sample is from a human subject. 
     
     
         22 . The method according to  claim 19 , wherein the neurodegenerative disease is selected from the group consisting of Alzheimer's disease, Huntington's disease and Parkinson's disease. 
     
     
         23 . The method according to  claim 19 , wherein said biological test sample comprises at least one cell type selected from the group consisting of circulating lymphocytes, a cell isolated from spinal fluid, olfactory neuroepithelial neuronal cell bodies or their neuronal processes, said cell expressing Beclin-1 protein in healthy subjects. 
     
     
         24 . The method according to  claim 19  further comprising the step of sequencing the gene encoding Beclin-1 in said biological test sample, wherein a mutation at position Thr119 is indicative of a neurodegenerative disease. 
     
     
         25 . A method for detecting a predisposition to a neurodegenerative disease in a subject, comprising obtaining a DNA sample from the subject, and determining whether an alteration is present in the sequence encoding Beclin-1, wherein a mutation at position Thr119 is indicative of a predisposition to a neurodegenerative disease. 
     
     
         26 .- 52 . (canceled) 
     
     
         53 . A kit for analyzing the level of Beclin-1 that is phosphorylated at position Thr119 in a biological test sample, comprising an antibody having specific binding affinity for a human Beclin-1 phosphorylated at residue Thr 119, or an antigen binding fragment thereof and instructions for performing the analysis, wherein the kit is identified for diagnosing degenerative diseases. 
     
     
         54 .- 55 . (canceled) 
     
     
         56 . The method of claim  1 , wherein the human Beclin-1 comprises the amino acid sequence as set forth in SEQ ID NO:1. 
     
     
         57 . The method of claim  1 , wherein the antibody is polyclonal. 
     
     
         58 . The method of claim  1 , wherein the antibody is monoclonal.